Lysine salt of the gadolinium-dota complex and its diagnostic applications

ABSTRACT

Lysine salt of the complex of gadolinium (III) of 1,4,7,10-tetraazacyclododecane-N,N&#39;,N&#34;,N&#39;&#34;-tetraacetic acid. Said salt has a low toxicity and may be used as diagnostic agent in magnetic resonance imaging.

The present invention is concerned with a new salt of thegadolinium(III)-DOTA complex and its applications to diagnostics ascontrast agent in magnetic resonance imaging (MRI) and in radiology byX-rays.

DOTA is the 1,4,7,10-tetra-azacyclododecane-N,N',N",N"'-tetra-aceticacid. The H[Gd-DOTA] complex has been mentioned by J. F. Desreux inInorg. Chem. 19, 1319, 1980. In addition, in FR-A-2 538 996, thepossibility has been mentioned of using the sodium salt and theN-methylglucamine salt of this complex as diagnostic agents.

There has now been found a new salt of this complex which offers in anunexpected way a particularly low toxicity and in particular, clearlyweaker than that of the N-methylglucamine salt.

The present invention has thus as its subject the lysine salt of thegadolinium(III)-DOTA complex.

This salt can be represented by the formula: ##STR1##

The salt according to the invention can be used as contrast agent inmagnetic resonance imaging and in radiology by X-rays.

The present invention therefore also has as its subject diagnosticcompositions, which can be administered to man, which include aneffective amount of the lysine salt of the gadolinium(III)-DOTA complex.

The compositions according to the invention can be administered to manby parenteral (notably vascular or lymphatic), sub-arachnoid, oral orintra-bronchial route.

For administration by parenteral or oral route, the compositionsaccording to the invention can notably be solutions of the salt in anaqueous physiologically acceptable solvent, these solutions containingnotably from 10⁻⁵ mole/l to 1 mole/l of the salt. The dose which can beadministered can generally be from 10⁻⁵ to 10⁻³ mole/kg.

For administration by intra-bronchial route, the compositions can beaerosols or suspensions.

The following examples illustrate the preparation of the salt accordingto the invention and compositions containing this salt.

1. Preparation of the H[GdDOTA], H₂ O complex

40.45 g of DOTA (0.1 mole) is added to a suspension composed of 18.13 gof gadolinium oxide Gd₂ O₃ (0.05 mole) in 400 cm³ of distilled water.

This suspension is taken to 70° C. under agitation for 20 hours,filtered on a 0.45 μm filter, then evaporated to dryness. The resultantpowder is taken up in ethyl ether, filtered, then dried under vacuum.

Analysis: (C₁₆ H₂₅ N₄ O₈ Gd, H₂ O)

    ______________________________________                                        Analysis: (C.sub.16 H.sub.25 N.sub.4 O.sub.8 Gd, H.sub.2 O)                                C %         N %    N %                                           ______________________________________                                        Calculated          33.37    4.71   9.72                                      Results             33.31    4.86   9.82                                      ______________________________________                                    

2. Preparation of a solution of the lysine salt of the H[GdDOTA], H₂ Ocomplex

27.93 g of the H[GdDOTA] complex is dispersed in an aqueous solution oflysine (7.91 g) at 20% by weight, by means of a magnetic agitation.

The volume is adjusted to 100 cm³ by addition of distilled water inorder to obtain a solution at 0.5 mole/l.

The solution is filtered on a 0.45 μm filter, then sterilized at 120° C.for 20 minutes.

Physico-chemical characteristics of the solution

Total quantity of gadolinium (determined by atomic absorptionspectrometry).

    [Gd]=0.501 mole/l

Quantity of traces of non-complexed gadolinium

    [Gd.sup.3+ ]<0.01%

Determination of the pH.

before sterilisation ph=7.6

after sterilisation ph=7.7

No variation after 3 months at ambient temperature.

Density at 20° C.

    D-1.1664

Osmolality obtained by cryoscopy at 20° C.

    1400 mosm/kg.

Further on there will be given results showing the particularly weaktoxicity of the salt according to the invention.

Acute toxicity by intra-venous route.

The acute toxicity has been determined on female mice (weight 20-25 g)of Swiss OF1 strain, by rapid intravenous injection (2 ml min⁻¹)according to the method of calculation defined by Reed and Muench in thequantal cumulative method AMJ.HYG. 27, 493, 1938. 6 animals were usedper dose with a minimum of 3 doses per trial, these doses following ageometric progression. The toxicity (LD₅₀) is noted 7 days after theinjection.

The results show a much clearer improvement in the case of the GdDOTAcomplex when passing from the N-methylglucamine salt to the lysine saltthan in the case of the GdDTPA complex (see EP-A-0 071 564) which wellshows the unexpected character of the particularly weak toxicity of thesalt according to the invention.

    __________________________________________________________________________                   Solution                                                                      concen-                                                                             Volume                                                                              Doses  LD.sub.50                                   Complex  Salt  tration.                                                                            injected                                                                            injected                                                                             mmoles/kg.                                  __________________________________________________________________________    H[GdDOTA]H.sub.2 O                                                                     N.methyl-                                                                           0.408 mole/1.                                                                       20-31.6                                                                             8-12.9 10.9                                                 glucamine   ml.kg.sup.-1                                                                        mmoles kg.sup.-1                                   H[GdDOTA]H.sub.2 O                                                                     Lysine                                                                              0.501 mole/1.                                                                       31.05-34.15                                                                         15.5-17.1                                                                            16.6                                                             ml.kg.sup.-1                                                                        mmoles kg.sup.-1                                   2H[GdDTPA]                                                                             N.methyl-                                                                           0.5 mole/1.                                                                         8.16-10                                                                             4.8-5  4.45                                                 glacamine   ml.kg.sup.-1                                                                        mmoles kg.sup.-1                                   2H[GdDTPA]                                                                             Lysine                                                                              0.5 mole/1.                                                                         10-13.55                                                                            5-6.7  5.94                                                             ml.kg.sup.-1                                             __________________________________________________________________________

We claim:
 1. The lysine salt of the gadolinium(III) complex of1,4,7,10-tetra-azacyclododecane-N,N',N",N"'-tetra-acetic acid.
 2. Anadministratable composition suitable for administration to humans as acontrast agent in magnetic resonance imaging and in radiologic X-rayimaging, said composition comprising an effective amount of the lysinesalt of the gadolinium (III) complex of1,4,7,10-tetra-azacyclododecane-N,N',N",N"'-tetra-acetic acid.
 3. Theadministratable composition of claim 2 comprising a solution of saidsalt in a physiologically acceptable aqueous solvent.
 4. Theadministratable composition of claim 3 wherein said solution comprisesfrom 10⁻⁵ mole/l to 1 mole/l of said salt.
 5. The administratablecomposition of claim 2 wherein said solution comprises from 10⁻⁵ mole/kgto 10⁻³ mole/kg.